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leptomeninges and underlying brain parenchyma may occur as late complications. Parenchymal lesions in the absence of skull and dural disease are uncommon (24-33).

SECONDARY (METASTATIC) INTRACRANIAL

LYMPHOMA

•80% from high-grade systemic B-cell lymphomas

•Skull, dural lesions > > brain parenchyma

○Multicompartmental disease common

○Calvaria + dural/epidural, scalp lesions

○Skull base + nose, cavernous sinus/pituitary

•Leptomeningeal, CSF spread uncommon

○Choroid plexus

○Ventricular ependyma

•Spine "drop metastases" (3-5%)

Diffuse leptomeningeal tumor spread and disseminated CSF lesions are relatively uncommon. Tumor spread along the

(24-31) Coronal T1 C+ FS in a patient with systemic DLBCL demonstrates enhancing metastatic lymphoma in the galea aponeurotica , calvarium , and duraarachnoid . (24-32) Coronal T1 C+ in a 75y man with systemic DLBCL shows multiple choroid plexus and ependymalmetastases. Diffuse dura-arachnoid metastases are also present.

(24-33A) Axial T1 C+ FS in a patient with cutaneous T-cell lymphoma shows multifocal enhancing masses in the parenchymaand choroid plexus . (24-33B) Coronal T1 C+ in the same case shows multifocal parenchymal, choroid plexus , and pial metastases .

optic nerve sheath is rare. Cranial neuropathies with multifocal enhancing cranial nerves occur as a late complication. Intradural lesions in the spine ("drop metastases") occur in 3- 5% of cases.

Histiocytic Tumors

Histiocytes belong to the group of mononuclear phagocytes and are defined as "tissue-resident" macrophages. Histiocytic CNS neoplasms are a heterogeneous group of tumors that are histologically and immunologically identical to their extracranial counterparts.

For decades, the histiocytoses were divided into Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytoses. With the discovery of recurrent BRAF mutations in LCH—later also found in Erdheim-Chester disease—the histiocytoses are

(24-34) Graphic depicts the well-defined lytic skull lesions that are characteristic of LCH. The lesions lack marginal sclerosis and show "beveled" edges .

now recognized as true neoplastic disorders with identifiable oncogenic drivers.

The histiocytoses are divided into five groups based on their histology, phenotype, and molecular alterations. The 2016 WHO classification recognizes five histiocytic tumors that affect the CNS: Langerhans cell histiocytosis, ErdheimChester disease, Rosai-Dorfman disease, juvenile xanthogranuloma, and histiocytic sarcoma. Because of its imaging similarities to these five recognized diseases, we also include a discussion of hemophagocytic lymphohistiocytosis in this section.

Langerhans Cell Histiocytosis

LCH can involve the CNS via direct invasion from the craniofacial bones, skull base, or meninges. Extraaxial masses of the hypothalamic-pituitary axis are also common, especially in the infundibular stalk. Parenchymal involvement is uncommon but portends high-risk disease.

LCH cells represent immature, partially activated dendritic Langerhans cells. Microglial cells are the intrinsic histiocytes of the brain and may participate in causing secondary neuronal damage, such as LCH-associated neurodegeneration.

Terminology

LCH is a clonal neoplastic proliferation of Langerhans cells. LCH was previously referred to as histiocytosis X.

Etiology

(24-35) Bone CT shows the classic appearance of LCH as a sharply marginated lytic calvarial lesion . Note the associated soft tissue mass .

patients. MAP2K1, which encodes MEK1, is mutated in 25% of cases.

Pathology

Location. Bone lesions are the most common manifestation of LCH (80-95% of cases) (24-34). Fifty percent are monostotic.

The craniofacial bones and skull base are the most commonly affected sites (55%), followed by the hypothalamic-pituitary region (50%), cranial meninges (30%), and choroid plexus (5%). Approximately one-third of patients exhibit parenchymal lesions. A leukoencephalopathy-like pattern, often with degenerative changes in the dentate nuclei and/or basal ganglia, occurs in nearly one-third of all LCH cases.

Size and Number. Size ranges from small calvarial lesions to extensive infiltrating masses that involve most of the skull base. Multiple lesions are found in 50% of cases.

Gross Pathology. Lesions are yellowish-white and vary from discrete dura-based nodules to granular, poorly defined parenchymal infiltrates.

Microscopic Features. Two major subtypes of CNS lesions occur in LCH: tumorous lesions and degenerative lesions. LCHrelated tumefactions contain a mixture of Langerhans cells and variable numbers of multinucleated histiocytes plus macrophages, lymphocytes, plasma cells, and occasionally eosinophils. Langerhans cells express S100 and vimentin as well as several histocyte markers.

Between 50 and 60% of patients with LCH have BRAF V600E mutations, but the RAF-MEK-ERK pathway is activated in all

LCH-related neurodegenerative lesions are most common in the brainstem and/or cerebellum. Langerhans cells are absent, while marked inflammatory changes with severe

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(24-36A) CECT in 15m girl with mastoid region swelling, central DI, and ataxia shows bilateral destructive temporal bone masses .

(24-36B) Axial T1 C+ FS in the same case demonstrates a thickened, enhancing infundibular stalk .

neuronal and axonal loss are present. Lesions consist of lymphocytes, activated microglia, and gliosis.

Staging, Grading, and Classification. LCH is now classified on the basis of disease extent as unifocal, multifocal (usually polyostotic), and disseminated disease.

Clinical Issues

Epidemiology. LCH is rare. The prevalence in children is estimated at 0.5 per 100,000 per year. Most cases with isolated lesions present in young children under 2 years of age with a M:F predominance of 2:1. Multifocal disease onset is generally between 2 and 5 years of age.

Presentation. The clinical presentation of LCH ranges from a self-healing bone lesion to multisystem life-threatening disease. Skin and bone lesions are the most frequent overall manifestations of LCH. Neurological involvement occurs in 20-50% of cases. Although isolated LCH does occur, most cases of CNS LCH are diagnosed concurrently with multisystem disease.

The most common presenting symptom of CNS LCH is central diabetes insipidus (DI), occurring in approximately half of all patients with multisystem LCH. Between 8-10% of children with central DI have LCH. Other CNSrelated findings include symptoms of increased intracranial pressure, cranial nerve palsies, seizures, visual disturbances, ataxia, and neurocognitive disturbances.

Natural History. Natural history and prognosis of classic LCH vary according to age at onset and whether the disease is isolated, multifocal, or disseminated. Solitary osseous lesions have the best prognosis, as spontaneous remission is relatively common. Overall survival rates are good although mortality in young children with multisystem disease approaches 15-20%.

Neurodegenerative LCH is generally a progressive disorder, with neurocognitive symptoms developing in about 25% of patients after 6 years. Malignant LCH exists but is very rare. Atypical organ involvement and an aggressive clinical course are characteristic.

LCH: ETIOLOGY, PATHOLOGY, AND CLINICAL FEATURES

Etiology

•Clonal neoplastic proliferation of Langerhans cells

•Most carry either BRAF V600E or MAP2K1 mutations

Pathology

•Neoplastic Langerhans cells, variable histiocytes, and inflammatory cells

○Craniofacial bones, 55%

○Hypothalamic-pituitary stalk, 50%

○Cranial meninges, 30%

○Choroid plexus, 5%

•Nonneoplastic neurodegenerative changes

○Cerebellum, basal ganglia, 35%

Clinical Features

•Solitary LCH children < 2 years old

•Multifocal LCH between 2 and 5 years

•Skin, bone lesions most common

•Central diabetes insipidus in 50%

Treatment Options. Therapeutic options depend on symptoms, location, and disease extent, ranging from simple surgical excision to radiation and chemotherapy.

Imaging

CT Findings. Craniofacial involvement is the most common presentation of CNS LCH. One or more sharply marginated lytic skull or facial bone defects are the most common manifestations on NECT (24-35), present in 55% of cases. A "beveled" appearance with the inner table more affected than the outer is typical.

Geographic skull base destruction, often centered on the temporal bone, may be extensive (24-36A). Associated soft tissue lesions may be small and relatively discrete, or they may be large, extensively infiltrating masses.

MR Findings. Soft tissue masses adjacent to calvarial vault or skull base lesions may show mild T1 shortening secondary to the presence of lipidladen histiocytes.

Abnormalities of the hypothalamus and pituitary stalk are common. The posterior pituitary "bright spot" is often absent, and the infundibular stalk may appear thickened (> 3 mm) and nontapering (24-36B). Lesions are slightly hyperintense on T2WI.

LCH enhances strongly and uniformly on T1 C+ scans. Look for a thickened enhancing infundibulum, dura-based masses, and choroid plexus involvement (24-37). Punctate foci of parenchymal enhancement occur in approximately 15% of cases (24-39), with the pons the most frequent site

(24-38).

Nontumorous neurodegenerative changes are common (24-39A). Secondary cerebellar degeneration occurs in 25% of cases and is seen as bilaterally symmetrical confluent T2/FLAIR hyperintensities, typically in the dentate nuclei (24-36C).

LCH: IMAGING

CT

•> 50% have lytic craniofacial lesion(s)

•"Beveled" lesion > geographic destruction

MR

•Soft tissue mass adjacent to bone lesion

•Hypothalamus/pituitary stalk

○Absent posterior pituitary "bright spot"

○Thickened (> 3 mm), nontapering stalk

•Enhancing lesions

○Dura-based mass(es)

○Choroid plexus

○Punctate/linear parenchymal enhancing foci

•Nontumorous degenerative changes

○Symmetric T2/FLAIR hyperintensity cerebellum/dentate nuclei, basal ganglia

Differential Diagnosis

The differential diagnosis varies with lesion site. Lytic calvarial lesions that may mimic LCH include burr holes and other surgical defects, dermoid and epidermoids, leptomeningeal cysts, and infection. With the exception of neuroblastoma, osseous metastases are relatively rare in children.

A thickened infundibular stalk can be seen with germinoma, the most important differential consideration in a child with central DI. Less common

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(24-37A) T2WI in a patient with LCH shows hypointense suprasellar , choroid plexus , and dural masses .

(24-37B) T1 C+ FS scan in the same patient shows that the lesions enhance intensely, slightly heterogeneously.

(24-37C) Sagittal T1 C+ shows the suprasellar mass involving the hypothalamus, infundibular stalk and infiltrating the pituitary gland .

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lesions with a thick nontapering stalk include neurosarcoid (uncommon in children), astrocytoma, and hypophysitis.

Erdheim-Chester Disease

Terminology

Erdheim-Chester disease (ECD) is a rare non-LCH histiocytosis characterized by xanthomatous infiltrates of foamy histiocytes.

Etiology

As 50-60% of patients with ECD have BRAF V600E mutations and activating MAP2K1 mutations are present in another 30%, the genetic parallels between ECD and LDH indicate a potential shared cell of origin for both conditions.

Pathology

Although it may affect multiple organs, ECD is most typically a disease of long bones. Extraskeletal manifestations occur in 50% of cases. Intracranial lesions are present in 10% of patients.

The brain, meninges, orbits, and sellar/juxtasellar region are all reported sites of ECD. Widespread infiltrative parenchymal lesions and dural thickening/meningioma-like mass(es) are the most common manifestations. Almost all patients with intracranial ECD also have facial and/or calvarial thickening.

Microscopically, ECD is characterized by infiltrates of lipidladen neoplastic histiocytes, multinucleated giant cells, scant lymphocytes, and variable fibrosis or gliosis. The histiocytes are CD68 positive and negative for CD1a and S100 protein.

Clinical Issues

ECD usually occurs in adults over 55 years of age. Prognosis in ECD is generally poor although treatment with interferon-α has improved survival in some patients.

Imaging

The hypothalamic-pituitary axis is involved in 50-55% of intracranial ECD (24-40). The pons and cerebellum—especially the dentate nuclei—are the second most common intraaxial location. Solitary or multiple durabased masses with or without diffuse pachymeningeal thickening occur in almost 25% of cases (24-40D). Osteosclerosis of the facial bones, calvaria, or vertebral column may be a specific feature suggesting the diagnosis.

Imaging in patients with hypothalamic-pituitary involvement shows absent posterior pituitary "bright spot" on T1WI. A focal

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suprasellar mass or nodular thickening of the infundibular stalk is common.

Meningioma-like dural masses are isointense on T1WI and isoto hypointense on T2WI. Strong homogeneous enhancement is typical.

Between 15-20% of ECD cases demonstrate parenchymal lesions. Multifocal areas of T2/FLAIR hyperintensity that show mild nodular enhancement on T1 C+ are typical findings. Ependymal enhancement with deep linear extension into the lentiform nuclei has been described as a finding suggestive of ECD.

A unique finding with ECD is perivascular disease. Periaortic fibrosis and perivascular infiltration along the carotid arteries extending into the cavernous sinus may occur. These lesions are very hypointense on T2WI and enhance strongly and intensely.

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Differential Diagnosis

The differential diagnosis of ECD includes meningioma and LCH. LCH is generally a disease of children, whereas ECD primarily affects middle-aged and older adults. Osteosclerosis of the facial bones and/or calvaria may be a unique feature of ECD although histologic analysis plays the definitive role in differentiating ECD from other histiocytoses. Wegener granulomatosis (WG) may mimic ECD with sinus, orbital, and meningeal lesions, but WG usually causes osteolysis, not osteosclerosis.

Rosai-Dorfman Disease

Terminology

Rosai-Dorfman disease (RDD), also called sinus histiocytosis with massive lymphadenopathy, is a rare benign

(24-40A) Axial NECT in a

39y man with proptosis shows bilateral intraconal retrobulbar soft tissue lesions. (24-40B) T2WI in the same case shows that the orbital lesions are very hypointense. Note welldelineated lobulated hypointense masses in the suprasellar cistern.

(24-40C) T1 C+ FS shows that the intraconal retrobulbar masses enhance intensely, as does the lobulated suprasellar mass. (24-40D) Sagittal T1 C+ FS in the same case shows extensive duralbased masses along falx, clivus, and diaphragma sellae and infiltrating the pituitary gland. Note enhancing lesions in the pons. This is biopsyproven Erdheim-Chester disease.

histioproliferative disorder of unknown etiology. BRAF V600E mutations are absent.

Pathology

RDD is now defined by the accumulation of CD68-positive, S100-positive, and CDE1a-negative proliferating histiocytes with intact, mature hematolymphoid cells floating freely within their cytoplasm ("emperipolesis"). A prominent lymphoplasmatic infiltrate is also frequently present within the tumor mass. The most common immunotypic feature of RDD is uniform, strong expression of S-100 protein in the absence of CD1a expression.

Clinical Issues

RDD can occur at any age, but almost 80% of patients are younger than 20 years old at the time of initial diagnosis. Bilateral massive but painless cervical lymphadenopathy is the most common presentation. CNS involvement is rare and

generally occurs without cervical adenopathy or other extranodal involvement.

Prognosis is generally favorable after surgical resection and/or corticosteroid treatment.

Imaging

RDD has a protean imaging appearance but most frequently presents as bilateral cervical lymphadenopathy. Extranodal involvement is seen in 50% of cases. The skin, nose, sinuses, and orbit (especially the eyelids and lacrimal glands) are often affected.

Intracranial RDD occurs in 5% of cases. Solitary or multiple dura-based masses that are moderately hyperdense on NECT and enhance strongly on CECT are typical findings. Sellar/suprasellar and intraspinal lesions are even less common. They can be isolated or occur in concert with more typical dura-based and/or orbital lesions.

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RDD is typically isointense with gray matter on T1WI and isoto slightly hypointense on T2WI. Lesions demonstrate high fractional anisotropy, low ADC, and mild "blooming" on SWI.

Intense homogeneous enhancement occurs following contrast administration (24-41). Less commonly, multiple cranial and peripheral enhancing nerves can be identified.

pMR is decreased. FDG PET shows variable uptake. Nodal and lacrimal disease shows avid uptake, but other sites are often "cold" on FDG PET.

Differential Diagnosis

Extracranial RDD closely resembles non-Hodgkin lymphoma. Reactive lymphadenopathy and TB adenopathy are common in children and may mimic RDD. Biopsy with histopathology is necessary for definitive diagnosis.

(24-41A) T1WI shows effaced sulci and GM-WM interfaces in both frontal lobes and along the interhemispheric fissure. (24-41B) T2WI shows lobulated parafalcine masses that are isoto slightly hyperintense relative to cortex.

(24-41C) Axial T1 C+ shows extensive, lobulated, intensely enhancing frontal and parafalcine masses . (24-41D) Coronal T1 C+ scan shows additional lesions over the convexity and along the leaves of the tentorium cerebelli. The patient had RosaiDorfman disease diagnosed by cervical lymph node biopsy.

The major imaging differential diagnosis of intracranial RDD is meningioma. pMR is helpful in distinguishing RDD, which is generally hypometabolic. Neurosarcoid with dura-based and sellar/suprasellar involvement can mimic RDD, as can other dural-based masses such as metastasis, plasma cell granuloma, infectious granuloma (e.g., TB), and IgG4-related disease.

Juvenile Xanthogranuloma

Terminology

Juvenile xanthogranuloma (JXG) is now considered a family of lesions that spans a spectrum from papular xanthoma and xanthoma disseminatum to cephalic histiocytosis and spindle cell xanthogranuloma.

Pathology

JXG are soft, yellowish or tan lesions that are composed of round or spindled, variably vacuolated neoplastic histiocytes, scattered giant cells, lymphocytes, and occasional eosinophils. JXGs are CD68 positive, CD1a and S100 negative, and factor XIIIa positive.

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(24-43) (Top) T2 scans in a 2y child with high fever and seizures show multiple patchy hyperintensities expanding the pons and both middle cerebellar peduncles, extending into the dentate nuclei and cerebellar hemispheres. (Bottom) T1 C+ SPGR scans for stereotactic localization prior to biopsy show diffuse confluent and patchy enhancement . Histopathologic diagnosis was hemophagocytic lymphohistiocytosis.

Clinical Issues

JXG generally affects young children and is usually limited to the skin. JXG may arise in the brain or cranial meninges, either with or without cutaneous manifestations. Cerebral lesions have been associated with multifocal or systemic forms of the disease, with an occasionally fulminant or relentless progressive clinical course.

Imaging

Imaging findings with JXG vary. Disseminated white matter lesions resemble those of LCH. Lesions may also affect the sellar region, choroid plexus, orbits, and paranasal sinuses. A rare disseminated form of xanthoma, called xanthoma disseminatum, preferentially affects young adults. The pituitary-hypothalamic axis and dura are most commonly affected by this variant (24-42).

Histiocytic Sarcoma

Histiocytic sarcoma is a rare, aggressive malignant neoplasm characterized by highly cellular noncohesive infiltrates of large, pleomorphic, mitotically active histiocytes. Reported cases of CNS histiocytic sarcoma have involved the brain parenchyma, meninges, and cavernous sinus. Isolated cases of

(24-44) Coronal graphic depicts the typical greenish discoloration of granulocytic sarcoma. Extradural and sinus disease is common. Parenchymal lesions in the basal ganglia, hypothalamus, and infundibular stalk are also illustrated.

radiation-associated histiocytic sarcoma involving the CNS have been reported.

Malignant fibrous histiocytoma is now considered a highgrade undifferentiated pleomorphic sarcoma and is no longer regarded as a true histiocytic lesion. Only isolated cases have been reported to involve the brain. Sarcomas and malignant mesenchymal tumors are discussed in detail in Chapter 22.

Hemophagocytic

Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is not a single disease but a clinical syndrome of life-threatening hyperinflammation. It can occur as a genetic defect (primary or familial HLH, which usually occurs in infancy as an autosomal-recessive disorder) or as a reactive infectionassociated process caused by viruses such as EBV, H1N1, and Bunyavirus. CNS HLH occurs in 30-70% of cases.

Terminology

Secondary HLH is also known as macrophage activation syndrome.

Etiology

Unlike the other histiocytic disorders, there is no specific cell marker for HLH. Specific mutations linked to HLH include perforin (FHL2) and UNC13D-FHL3 gene mutations. The mutation for X-linked lymphoproliferative disorder involves the SH2D1A gene.

(24-45) Autopsy specimen shows dural thickening, infiltration, and focal masses in a patient who died from AML. (Courtesy R. Hewlett, MD.)

Although its pathogenesis is not fully understood, HLH may be mediated by excessive activation of CD8+ T lymphocytes and the release of cytokines such as TNF-α and interferon-γ.

Pathology

HLH is characterized by aggressive proliferation of activated macrophages and histiocytes that infiltrate the brain and meninges. Perivascular infiltration follows the initial leptomeningeal inflammation. Eventually, massive parenchymal infiltration, blood vessel destruction, and tissue necrosis ensue. Hemophagocytosis, the histologic hallmark of the disease, may be scant or even absent early in the disease course.

Clinical Issues

HLH is primarily a disease of infants and young children. Fever, hepatosplenomegaly, and cytopenias characterize the disease. The typical clinical presentation includes irritability, bulging fontanelle, seizures, cranial nerve palsies, ataxia, and hemiplegia. Primary HLH is lethal without allogenic stem cell transplantation. Secondary HLH is usually self-limited.

Imaging

CNS involvement is present in at least 75% of all HLH patients at the time of initial diagnosis. Imaging shows extensive confluent T2/FLAIR hyperintense infiltrates in the cerebellum and cerebral white matter (24-43). Symmetric periventricular lesions without thalamic and brainstem involvement are common in primary HLH. Linear and nodular enhancement of parenchymal lesions and the pial surfaces of the brain is typical.

Hematopoietic Tumors and

Tumor-Like Lesions

Leukemia

Leukemia is the most common form of childhood cancer, representing approximately one-third of all cases. Acute lymphoblastic leukemia (ALL) accounts for 80% and acute myeloid leukemia (AML) for most of the remaining 15-20%. Chronic myelocytic leukemia (CML) and lymphocytic leukemia are much more common in adults. Regardless of specific type, the general clinical features of leukemias are similar.

Once relatively uncommon, the prevalence of CNS involvement has risen with treatment advances that result in prolonged overall survival. Neurological symptoms in leukemia patients may be due to CNS involvement (direct or primary effects) or occur as treatment complications (secondary effects).

Treatment-related complications include white matter lesions, mineralizing microangiopathy, posterior reversible encephalopathy syndrome (PRES), secondary tumors, infections, and brain volume loss. These are considered separately in Chapter 30. Here we consider the direct effects of leukemia on the CNS.

Terminology

Leukemic masses containing primitive myeloblasts, promyelocytes, or myelocytes were initially called chloromas (for the greenish discoloration caused by high levels of myeloperoxidase in these immature cells). As 30% of the cells are other colors (white, gray, or brown), these tumors have been renamed granulocytic (myeloid) sarcomas.

Etiology

Granulocytic sarcoma is often diagnosed simultaneously with or immediately after the onset of acute leukemia. In patients without overt leukemia, granulocytic sarcoma usually presages the development of AML by several months. Other conditions that predispose to the development of granulocytic sarcoma are myelodysplastic syndromes and nonneoplastic myeloproliferative disorders, such as polycythemia vera, hypereosinophilia, and myeloid metaplasia.

Intracranial granulocytic sarcomas probably develop when neoplastic cells in the calvaria migrate via haversian canals through the periosteum and into the dura to form focal leukemic masses. If the pial-glial barrier is breached, tumor can spread directly or via the perivascular spaces into the underlying brain.

Extramedullary leukemia (EML) is common in children with leukemia. CNS involvement is rare and occurs either as leukemia cells within the CSF or as focal aggregates of immature myeloid cells that infiltrate bone and soft tissues.

Pathology

Location. EML can affect virtually any part of the body, including the skin, lymph nodes, stomach, and colon. Multiple lesions are common. Lesions of the vertebrae, orbits, and calvaria are more common than intracranial deposits, which are relatively rare.

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(24-46A) NECT in a 28y man with AML and a scalp "lump" shows left frontal subgaleal and hyperdense extraaxial mass .

(24-46B) Bone CT with edge enhancement shows permeative, destructive changes in the adjacent calvarium .

(24-46C) Prebiopsy T1 C+ SPGR shows the subgaleal/calvarial/epidural mass enhances intensely. Note small dural "tails" ; chloroma.

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(24-47A) NECT scan in a child with AML shows a hyperdense midline frontal mass with peritumoral edema and bone destruction .

(24-47B) T2WI shows the mass , permeative destructive bone lesion , and parenchymal mass that is isointense with cortex.

(24-47C) The lesion enhances strongly, mostly uniformly on T1 C+. This is granulocytic sarcoma ("chloroma").

Between 5-7% of patients with AML have asymptomatic CNS involvement as evidenced by positive CSF cytological analysis. Overt CNS leukemia presents in three forms: (1) meningeal disease ("carcinomatous meningitis"), (2) intravascular tumor aggregates with diffuse brain disease ("carcinomatous encephalitis"), and (3) focal tumor masses (granulocytic sarcoma).

Most intracranial lesions are located adjacent to malignant deposits in the orbits, paranasal sinuses, skull base, or calvaria. Intraaxial granulocytic sarcomas occur but are less common (24-44).

Size and Number. Multifocal involvement is typical. Extraaxial lesions are generally large and seen as extensive bony infiltrates and dura-based masses (24-45). Parenchymal lesions are usually smaller, ranging from a few millimeters to 1 or 2 cm.

Microscopic Features. Granulocytic sarcomas are highly cellular tumors that consist of leukemic myeloblasts and myeloid precursors embedded in a rich reticulin-fiber network. Monotonous tumor cells with large nuclei, prominent nucleoli, and scanty eosinophilic cytoplasm are typical. Nuclei are often pleomorphic. Multiple mitoses are typical, with MIB-1 labeling exceeding 50%.

Clinical Issues

Epidemiology and Demographics. Granulocytic sarcoma occurs in 3-10% of patients with AML and 1-2% of patients with CML. Intracranial and intraspinal lesions in the absence of systemic disease are very rare. Although granulocytic sarcoma can affect patients of virtually any age, 60% are younger than 15 years at the time of initial diagnosis.

Presentation. The typical clinical setting is that of a child with AML who develops headache or focal neurologic deficits. Meningeal disease may occur in adults with either acute or chronic myelogenous leukemia. Cranial nerve palsies are typical symptoms.

Natural History. Although the overall survival in treated AML is 40-50%, development of granulocytic sarcoma implies blastic transformation and poor prognosis. Transformation of chronic lymphocytic leukemia (CLL) into diffuse large non-Hodgkin lymphoma (Richter syndrome) is a rare but serious complication. Median survival in transformed CLL is 5 or 6 months despite multiagent therapy.

Treatment Options. Patients with AML presenting with granulocytic sarcoma may benefit from individually tailored regimens with risk-adapted chemotherapy, postinduction intensification of therapy, hematopoietic stem cell transplantation, and prolonged treatment maintenance.

Imaging

Imaging is key to the diagnosis of CNS involvement, as CSF studies may be negative.

CT Findings. Granulocytic sarcomas typically present as one or more isoor hyperdense dura-based masses on NECT (24-46A). Strong uniform enhancement is typical. Bone CT often shows infiltrating, permeative, destructive lucent lesions (24-46B). An adjacent soft tissue mass may be present.

MR Findings. Nearly 75% of patients with leukemia and positive CSF cytology have abnormal findings on MR (24-46C) (24-47). Pachymeningeal (30%), leptomeningeal (25%), cranial nerve (30%) (24-50), and spinal meningeal (70%) types of enhancement are typical.

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(24-51A) FLAIR in a 26y man with ALL, HA, and altered mental status appears normal.

(24-51B) T2* GRE in the same case shows punctate hypointensities in the corpus callosum.

(24-51C) T2* SWI shows innumerable blooming foci throughout the brain. These are leukemiaassociated microbleeds.

Parenchymal lesions ("chloroma") are much less common than meningeal disease. Chloromas are hypoto isointense on T1WI and heterogeneously isoto hypointense on T2/FLAIR (24-48) (24-50). FLAIR is helpful in detecting pial, perivascular, and CSF spread. Hemorrhage is common and easily detected on T2* (GRE, SWI) imaging (24-51).

Enhancement of parenchymal (24-49) and focal dural chloromas (24-47C) is typically strong and relatively homogeneous. Fat-saturated postcontrast T1 scans are especially helpful in detecting osseous involvement and delineating its extent. Because of its cellularity, granulocytic sarcoma often demonstrates diffusion restriction.

Nuclear Medicine Findings. Tc-99m MDP is commonly used to detect bone disease. Whole-body FDG PET or fused PET/CT shows avid uptake and is useful for initial staging as well as assessing treatment response.

Differential Diagnosis

Differential diagnosis depends on location. Dura-based granulocytic sarcomas may resemble extraaxial hematoma, lymphoma, or meningioma.

In younger children, metastatic neuroblastoma and Langerhans cell histiocytosis can mimic granulocytic sarcoma. Extramedullary hematopoiesis is a diagnostic consideration but is typically more hypointense than granulocytic sarcoma on T2WI.

Parenchymal granulocytic sarcomas or "chloromas" are much less common than dura-based lesions. The major differential diagnosis of granulocytic sarcoma is lymphoma or (in older patients) metastasis.

CNS LEUKEMIA

Terminology and Etiology

•Leukemia = most common childhood cancer

○Acute lymphoblastic leukemia (ALL) (80%)

○Acute myeloid leukemia (AML) (20%)

○Chronic leukemias generally in adults

•CNS leukemias are extramedullary leukemias

Pathology and Clinical Issues

•CNS leukemia disease spectrum

○Meningeal disease

○Diffuse parenchymal disease (rare)

○Granulocytic sarcoma (focal leukemic mass)

•Location

○Extraaxial, dura-based > parenchymal

○Typically by malignant deposits in skull, orbit, sinuses

○Multiple lesions, multiple compartments typical

•Presentation varies; asymptomatic, positive CSF (5-7%)

○CNS involvement in 3-10% of patients with AML

Imaging

•NECT

○Permeative destructive bone lesions

○Hyperdense dural masses (parenchymal disease rare)

•MR

○Hypo-/isointense to brain on T1

○Heterogeneously iso-/hyperintense on T2

○± Hemorrhage on T2* (GRE, SWI)

○Enhances strongly

○DWI often positive

•Whole-body FDG PET, PET/CT

○Useful for staging, assessing treatment response

Plasma Cell Tumors

Plasma cell myeloma and related immunosecretory disorders are a group of B-cell clonal proliferations characterized by production of monoclonal immunoglobulin from immortalized plasma cells.

Three major forms of neoplastic plasma cell proliferations are recognized: (1) solitary bone plasmacytoma (SBP), (2) solitary extramedullary plasmacytoma (EMP), and (3) multiple myeloma (MM).

SBPs are sometimes simply called plasmacytoma or solitary plasmacytoma (SP). SPs are characterized by a mass of neoplastic monoclonal plasma cells in either bone or soft tissue without evidence of systemic disease. SPs are rare (5-10% of all plasma cell neoplasms) and are most commonly found in the vertebrae and skull.

EMP is usually seen in the head and neck, typically in the nasal cavity or nasopharynx.

Multifocal disease is MM (24-52). Plasmablastic lymphoma is an uncommon, aggressive lymphoma that most frequently arises in the oral cavity of HIV-infected patients. Rarely, atypical monoclonal plasma cell hyperplasia occurs as an intracranial inflammatory pseudotumor (discussed in Chapter 28).

Etiology

Although the etiology of plasma cell tumors remains unknown, there is good evidence for a multistep transformation process that corresponds to clinically discernible disease stages.

Monoclonal gammopathy is a common asymptomatic precursor lesion that carries a 1% annual risk for progression to frank plasma cell neoplasms. Terminal stages in plasma cell neoplasms are characterized by increasing genetic complexity and independence from bone marrow stromal cells.

Pathology

Location. SBPs almost always occur in red marrow, most frequently in the spine. The skull is the next most common location in the head and neck.

EMPs in the presence of MM are uncommon (4-5% of cases) and rarely involve the CNS. Myelomatous involvement of the CNS is rare, with less than 1% of patients having identifiable CNS involvement (presence of atypical plasma cells in CSF and/or identification of meningeal or intraparenchymal disease on MR).

Gross and Microscopic Features. Gelatinous red-brown tissue replaces normal-appearing yellow marrow. Trabecular bone loss is usually apparent. Microscopic examination discloses monotonous sheets of uniform welldifferentiated neoplastic plasma cells with eccentric nuclei and basophilic cytoplasm. At least 10% of the cells in a bone marrow biopsy specimen must be plasma cells for definitive diagnosis of MM.

Approximately 60% of MMs produce IgG, 20-25% produce IgA, and 15-20% produce free immunoglobulin light chains.

Staging, Grading, and Classification. The two most commonly used myeloma staging systems are the Durie-Salmon PLUS classification and the International Staging System (ISS). Durie-Salmon PLUS integrates clinical, laboratory, and histopathologic parameters with imaging features.

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(24-52) Graphic shows multiple lytic foci characteristic of MM. Sagittal section shows the "punched-out" lesions in the diploic space .

(24-53) Bone CT shows MM. Innumerable lytic "punched-out" lesions give the calvaria the characteristic "salt and pepper" appearance.

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(24-55A) Sagittal NECT in a 67y man with multiple cranial neuropathies shows hyperdense, destructive central skull base mass .

(24-55B) Sagittal T1 C+ MR shows the mass enhances intensely and uniformly. Note engulfment, infiltration of the pituitary gland .

(24-55C) Axial T2WI shows the extent of the destructive mass , which is mildly hypointense relative to GM. This is plasmacytoma.

Clinical Issues

Epidemiology. MM is the most common primary bone malignancy, accounting for approximately 10% of all hematologic malignancies. Almost half of all SBPs eventually progress to MM.

Intracranial MM is uncommon and is usually secondary, occurring mostly as extension into the dura and leptomeninges from osseous lesions in the calvaria, skull base, nose, or paranasal sinuses.

Primary CNS plasmacytoma is very rare. Waldenström macroglobulinemia (a.k.a. Bing-Neel syndrome) may form dural lesions that then invade the brain parenchyma.

Demographics. Prevalence varies with the type of plasma cell proliferation but generally rises with advancing age. Median age of patients with SBP or EMP is 55 years. The vast majority of patients with MM are older than 40 years with peak age at presentation in the seventh decade. There is a slight female predominance for SBP and a moderate male predominance in EMP and MM.

Presentation. The most common presentation is bone pain. Constitutional symptoms such as fever of unknown origin are common with MM. Cranial nerve involvement is rare but may develop secondary to skull base plasmacytoma.

Immunoelectrophoresis detects M protein in the serum and/or urine from 99% of patients.

Natural History. Many plasma cell tumors eventually transform into MM. The 5-year survival rate of MM is 20%. With newer treatment regimens, median survival has increased from 2 or 3 years to 4 years. Death is usually secondary to renal insufficiency, infection, and thromboembolic events.

Treatment Options. Treatment depends on disease stage. Evaluation of clinical, morphological, immunophenotypical, and cytogenetic features is necessary for individual risk assessment and appropriate therapy.

PLASMA CELL TUMORS: PATHOLOGY

Pathology

•Solitary bone plasmacytoma (SBP)

•Multifocal disease = multiple myeloma (MM)

•Red marrow sites (spine > skull)

Durie-Salmon PLUS Staging (MM)

•Monoclonal gammopathy

○< 10% plasma cells in bone marrow

○Normal marrow on MR, PET/CT

•Smoldering MM

○≥ 10% plasma cells in bone marrow

○Limited marrow disease on MR, PET/CT

•MM

○≥ 10% plasma cells and/or plasmacytoma + end-organ damage

○Focal or diffuse lesions on MR

○↑ FDG marrow uptake (multifocal or diffuse)

Imaging

Although radiography can only detect trabecular bone loss of more than 3050%, skeletal surveys are still widely used for staging and surveillance of plasma cell tumors. CT is the best procedure for delineating lytic lesions in the skull base or calvaria.

MR is best used to evaluate the presence of diffuse marrow infiltration and define the extent of soft tissue disease. Whole-body MR is helpful in detecting systemic disease that would indicate the diagnosis of MM instead of solitary plasmacytoma.

CT Findings. SBPs are intramedullary soft tissue masses that produce lytic lesions centered in bone marrow. NECT shows a "punched-out" lesion without sclerotic margins or identifiable internal matrix. Cortical breakthrough with formation of a soft tissue mass adjacent to the lytic lesion may be present.

MM shows numerous lytic lesions (24-53), usually centered in the spine, skull base, calvarial vault, or facial bones (24-54) (24-55A). A variegated "salt and pepper" pattern is typical.

Diffuse osteopenia without focal lesions is seen in 10% of MM cases.

MR Findings. In staging MM, the extent of bone marrow involvement is assessed on T1WI. Whole-body MR has emerged as the most sensitive imaging modality for detecting diffuse and focal bony lesions.

Osseous lesions replace normal hyperintense fatty marrow and are typically hypointense on T1WI. T2 and fat-saturated sequences such as T2-weighted STIR imaging also highlight the extent of marrow infiltration (24-55C). Focal and diffuse lesions appear hyperintense. Both SBPs and MM enhance strongly following contrast administration (24-55B). Leptomeningeal and parenchymal disease occurs but is uncommon (24-56).

Nuclear Medicine. Bone scintigraphy is not useful in evaluating MM, as lesions are often "cold" on Tc-99m scans. PET/CT is especially helpful for identifying and localizing extramedullary lesions. Sensitivity is 96% with a specificity of almost 80%.

Differential Diagnosis

Multiple "punched-out" destructive myeloma lesions can appear virtually identical to lytic metastases. Spine and skull base MM can resemble leukemia or non-Hodgkin lymphoma. Invasive pituitary macroadenoma may be difficult to distinguish from MM, as both are isointense with gray matter. An elevated prolactin is often present with macroadenoma, and the pituitary gland cannot be separated from the mass.

PLASMA CELL TUMORS: CLINICAL ISSUES, IMAGING, AND DDx

Clinical Issues

•Monoclonal gammopathy is common precursor lesion

•1% annual risk of developing plasma cell neoplasm

•Generally older adults

•Approximately 50% of SBPs progress to MM

•MM 5-year survival = 20%

Imaging

•NECT

○Solitary or multiple "punched-out" lytic lesion(s)

○± Soft tissue mass

•MR

○Lesions replace normal fatty marrow

○Hypointense on T1-, T2WI

○Enhance on T1 C+ FS

Differential Diagnosis

•Lytic metastases (extracranial primary)

•Leukemia, lymphoma

•Invasive pituitary macroadenoma (central skull base)

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(24-56A) FLAIR in a patient with Waldenström macroglobulinemia shows hyperintense sulci, edema in the left hemisphere .

(24-56B) T1 C+ scan shows an enhancing duraarachnoid mass with enhancement of the underlying sulci .

(24-56C) T1 C+ FS shows diffuse dura-arachnoid thickening and lymphoplasmacytic infiltrate in meninges. (Courtesy P. Hildenbrand, MD.)

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(24-57) Graphic shows extramedullary hematopoiesis, hematopoietic calvarial marrow, and lobulated extraaxial masses .

(24-58A) EMH shows smooth dura-based mass with small dural "tails" . Bluish discolorationsare from blood-forming elements.

Extramedullary Hematopoiesis

Extramedullary hematopoiesis (EMH) is the compensatory formation of blood elements due to decreased medullary hematopoiesis. Various anemias (thalassemia, sickle cell disease, hereditary spherocytosis, etc.) are the most common etiologies, accounting for 45% of cases. Myelofibrosis/myelodysplastic syndromes (35%) are the next most common underlying causes associated with EMH.

Multiple smooth, juxtaosseous, circumscribed, hypercellular masses are typical (24-57) (24-58). The most common site is along the axial skeleton. The face and skull are the most common head and neck sites. The subdural space is the most common intracranial location.

EMH is hyperdense on NECT (24-59A), enhances strongly and homogeneously on CECT, and may show findings of underlying disease on bone CT (e.g., "hair on end" pattern in thalassemia, dense bone obliterating the diploic space in osteopetrosis).

Round or lobulated subdural masses that are isoto slightly hyperintense relative to gray matter on T1WI and hypointense on T2WI are typical (2459B). EMH enhances strongly and uniformly on postcontrast T1WI (24-59C).

The major differential diagnoses of intracranial EMH are dural metastases and meningioma. Neurosarcoid and lymphoma are other considerations.

EXTRAMEDULLARY HEMATOPOIESIS

Etiology

•Decreased medullary hematopoiesis

•Compensatory formation of blood elements

•Anemias (45%), myelofibrosis/myelodysplasia (35%)

Pathology

•Multiple smooth juxtaosseous masses

•Spine, face, skull, dura

Imaging

•Hyperdense on NECT

•T1 iso-/hypo-, T2 hypointense

•Enhances strongly

Differential Diagnosis

•Dural metastases

•Meningioma

•Neurosarcoid

•Lymphoma